Deoxystreptamine-based aminoglycosides are a clinically important class of antibiotics that are effective against a broad range of microorganisms (Edson, R. S.; Terrel, C. L. Mayo Clin. Proc. 1991, 66, 1158). It is believed that aminoglycosides exert their therapeutic effect by interfering with translational fidelity during protein synthesis via interaction with the A-site rRNA on the 16S domain of the ribosome (Moazed, D.; Noller, H. F. Nature 1987, 327, 389; Purohit, P.; Stern, S. Nature 1994, 370, 659; Formy, D.; et al. Science 1996, 274, 1367). Unfortunately, the high toxicity and rapid emergence of high level aminoglycoside resistance have severely limited the usefulness of this class of antibiotics. Numerous aminoglycoside resistance mechanisms have been identified, and enzymatic acetylation, phosphorylation and ribosylation are the primary causes of high level resistance in most clinical isolates (Wright, G. D.; et al. Adv. Exp. Med. Biol. 1998, 456, 27; Kondo, S.; Hotta, K. J. Infect. Chemother. 1999, 5, 1; Mingeot-Leclerco, M.-P.; et al. Antimicrob. Agents Chemother. 1999, 43, 727). Of the modifying enzymes, the acetyl- and phosphotransferases (AAC and APH) have been extensively studied with respect to their specificity (Wright, G. D.; et al. Adv. Exp. Med. Biol. 1998, 456, 27; Kondo, S.; Hotta, K. J. Infect. Chemother. 1999, 5, 1; Mingeot-Leclerco, M.-P.; et al. Antimicrob. Agents Chemother. 1999, 43, 727; Daigle, D. M.; et al. Chem. Biol. 1999, 6, 99; Azucena, E.; et al. J. Am. Chem. Soc. 1997, 119, 2317; Patterson, J.-E.; Zervos, M. J. Rev. Infect. Dis. 1990, 12, 644).
What was needed was a method to tackle the problem of antibiotic resistance. What was needed was bifunctional aminoglycosides that can resist or inhibit aminoglycoside-modifying enzymes while simultaneously targeting ribosomal RNA.